[Frontiers of Neurology and Neuroscience] The Hippocampus in Clinical Neuroscience Volume 34 () || What Animals Can Teach Clinicians about the Hippocampus

Structure and Physiology of the Animal and Human Hippocampus

Szabo K Hennerici MG (eds) The Hippocampus in Clinical Neuroscience Front Neurol Neurosci Basel Karger 2014 vol 34 pp 36ndash50 (DOI 101159000356418)

AbstractAbnormalities in hippocampal structure and function have been reported in a number of human neuropathological and neurodevelopmental disorders including Alzheimerrsquos disease autism spec-trum disorders Down syndrome epilepsy and schizophrenia Given the complexity of these disor-ders animal studies are invaluable and remain to date irreplaceable providing fundamental knowl-edge regarding the basic mechanisms underlying normal and pathological human brain structure and function However there is a prominent ill-conceived view in current research that scientists should be restricted to using animal models of human diseases that can lead to results applicable to humans within a few years Although there is no doubt that translational studies of this kind are im-portant and necessary limiting animal studies to applicable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems Here we discuss findings regarding the normal postnatal development of the monkey hippocampal forma-tion which provide an essential framework to consider the etiologies of different neuropathological disorders affecting human hippocampal structure and function We focus on studies of gene expres-sion in distinct hippocampal regions that shed light on some basic mechanisms that might contrib-ute to the etiology of schizophrenia We argue that researchers as well as clinicians should not con-sider the use of animals in research only as lsquoanimal modelsrsquo of human diseases as they will continue to need and benefit from a better understanding of the normal structure and functions of the hip-pocampus in lsquomodel animalsrsquo copy 2014 S Karger AG Basel

Experimental studies conducted with animals are invaluable and remain to date irre-placeable providing some of the fundamental knowledge regarding the basic mecha-nisms underlying normal and pathological human physiology The study of the brain and the hippocampus in particular is no exception and most of the information re-

What Animals Can Teach Clinicians about the Hippocampus

Pierre Lavenex

a b Pamela Banta Lavenex

a Greacutegoire Favre

Laboratory for Experimental Research on Behavior Institute of Psychology University of Lausanne Lausanne and b Laboratory of Brain and Cognitive Development Fribourg Center for Cognition University of Fribourg Fribourg Switzerland

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What Animals Can Teach Clinicians about the Hippocampus 37

garding the basic structure and functions of the hippocampal formation have derived from animal studies [1] Over the years however a gradual shift has occurred in the type of scientific studies performed with animals going from descriptive studies of the organization of the nervous system to experimental studies of normal brain func-tion to animal models of human disease

Currently a prominent ill-conceived view of which research with animals should be encouraged funded or even allowed posits that scientists should be restricted to only using animal models of human diseases that can lead to results applicable to humans within a few years Although there is no doubt that translational studies of this kind are important and necessary limiting animal studies to currently appli-cable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems Moreover defining what is dis-pensable in science and foreseeing which experiment will lead to truly applicable results are very difficult and often likely to be wrong Failure is part of the scien-tific endeavor and should be embraced as much as success as long as we have a chance to gain new knowledge by performing an experiment or making an obser-vation

A perfect example of this is the discovery of penicillin by Sir Alexander Fleming in 1928 It was a failed experiment the accidental contamination of a bacteria cul-ture plate by a mold that led to the isolation and identification of this widely-used antibacterial substance In his Nobel Prize acceptance speech in 1945 Fleming de-clared

We all know that chance fortune fate or destiny ndash call it what you will has played a consider-able part in many of the great discoveries in science We do not know how many for all scientists who have hit on something new have not disclosed exactly how it happened We do know though that in many cases it was a chance observation which took them into a track which eventually led to a real advance in knowledge or practice This is especially true of the biological sciences for there we are dealing with living mechanisms about which there are enormous gaps in our knowl-edge

Many scientists including a number of other Nobel laureates have shared his view Furthermore to date there are still enormous gaps in our knowledge of normal brain structure and functions

Here we very humbly discuss the continuous need to obtain fundamental infor-mation regarding how the normal brain is built and works We argue that researchers as well as clinicians should not consider the use of animals in research only as lsquoanimal modelsrsquo of human diseases since science and medicine in particular will continue to need and indeed will benefit greatly from a better understanding of the structure and function of biological systems in various organisms or lsquomodel animalsrsquo Given the fo-cus of this book on the hippocampus we consider specific examples illustrating how fundamental knowledge of the normal patterns of postnatal development of the mon-key hippocampal formation can shed light on the etiologies of human diseases affect-ing hippocampal structure and function

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38 Lavenex middot Banta Lavenex middot Favre

The Primate Hippocampus Structure

The terms lsquohippocampusrsquo and lsquohippocampal formationrsquo are often used interchange-ably yet they refer to and include different brain structures depending on the context in which they are used Here we do not provide an exhaustive and detailed descrip-tion of the structural characteristics of the hippocampus as this has already been done [2ndash4] We use the definition of the hippocampal formation as a group of cortical re-gions located in the medial temporal lobe that includes the dentate gyrus hippocam-pus (CA3 CA2 CA1) subiculum presubiculum parasubiculum and entorhinal cor-tex (fig 1) Each of these structures contains a number of different cell types and dif-ferent sets of intrinsic connections as well as interconnections with other brain regions both of which exhibit clear and distinct topographical distributions Alto-gether these interconnected structures form a functional brain system essential for memory which is particularly sensitive to a number of pathologies [4]

As mentioned above most of the information regarding the structural organiza-tion of functional hippocampal circuits is derived from experimental work performed with animals in particular rodents but also monkeys Similarly animal models are typically used to study the molecular and cellular basis of pathologies affecting human hippocampal structure and function Consequently it is important to be aware of the similarities and differences between species in order to extrapolate from the findings of fundamental research in animals to clinical problems in humans [4]

For example let us consider that an experimental study in rats reveals that the commissural projections which originate in the polymorphic layer of the dentate gyrus and are prominent throughout the entire septotemporal (long) axis of the rat dentate gyrus play an important role in the generation or spread of epileptic sei-zures throughout the hippocampal network These findings will be very difficult to extrapolate to humans and are very unlikely to have any direct clinical impact since the commissural projections of the primate (including humans) dentate gyrus are extremely limited and originate only from its most rostral (or uncal) portion Rats are not monkeys and monkeys are not humans However brain structures and functions that are conserved between rats and monkeys are likely to be conserved in humans One striking example is the central role of the hippocampus in allocentric spatial learning and memory processes [5ndash7]

To be extremely clear we are not arguing that experimental work aimed at under-standing the fundamentals of brain structure and functions should not be performed in rodents However great care must be taken when extrapolating results from one species to another [8 9] Rhesus monkeys with their phylogenetic proximity to hu-mans represent an unparalleled model in which empirical and systematic investiga-tions of the normal and pathological development of brain-cognition interactions can be undertaken Nonhuman primate research is thus particularly important to bridge potential gaps between experimental studies in rodents and clinical applications in humans

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The Primate Hippocampus Development

Understanding the normal development of the hippocampal formation can provide invaluable information about its functions and its susceptibility to pathologies across the lifespan [4 7] Until recently there was little information on the structural de-velopment of the different regions of the primate hippocampal formation and the

Rat Monkey Human

Fig 1 a Schematic representation of the hierarchical organization of the main serial and parallel pathways through the different regions of the rhesus macaque monkey (Macaca mulatta) hippo-campal formation EC = Entorhinal cortex DG = dentate gyrus CA3 CA2 CA1 = fields of the hippo-campus proper Sub = subiculum PrS = presubiculum PaS = parasubiculum Scale bar = 1 mm b Volume-rendered MRI of rat monkey and human brains illustrating the relative positions of the dentate gyrus + hippocampus + subiculum (in red) and the entorhinal cortex (in green) MRI of the rat brain courtesy of Dr G Allan Johnson Center for In Vivo Microscopy Duke University NIHNCRR National Resource (P41 05959)

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impact of their maturation on the emergence of particular functions [7] For exam-ple in the case of developmental amnesia patients who sustained hippocampal dam-age early in life exhibit memory impairments affecting preferentially episodic mem-ory (the memory for autobiographical events) whereas semantic memory (the memory for facts about the world) is somehow preserved [10] In contrast a hippo-campal lesion in adults generally impairs both semantic and episodic memory pro-cesses [11] We have shown similar functional plasticity in monkeys that received hippocampal lesions early in life Hippocampal lesions prevent spatial relational learning in adult-lesioned monkeys [5] whereas spatial relational learning persists following neonatal lesions [12] Preliminary findings from our laboratory suggest that significant reorganization of specific brain circuits might contribute to the recovery of function following early but not late lesions [Lavenex et al unpubl data] Now we briefly discuss our findings regarding the normal postnatal development of the mon-key hippocampal formation [13 14] (fig 2) that provide an essential framework to consider the etiologies of different neurodevelopmental disorders affecting human hippocampal structure and functions

Neurogenesis in the Dentate GyrusThe dentate gyrus is one of only two regions of the mammalian brain where sub-stantial neurogenesis occurs postnatally (rats [15] monkeys [16] humans [17]) In a first study [13] we demonstrated that about 40 of the total number of granule cells found in 5- to 10-year-old monkeys are added to the granule cell layer postna-tally with a peak (about 25) in the first 3 months after birth We also found sig-nificant levels of cell proliferation neurogenesis and cell death in the context of an overall stable number of granule cells in mature monkeys The overall distribution of cell proliferation that we described in newborn monkeys was similar to that ob-served in newborn humans [18] Importantly we established that the developmental period during which a significant number of neurons are added to the monkey gran-ule cell layer is longer than previously thought [16] In the absence of strict quanti-fication of human cases older than 1 year of age our findings in monkeys suggest that sustained levels of developmental neurogenesis might continue and impact the dentate gyrus structure until at least 4 years of age in humans Importantly we also estimated the number of new neurons that could potentially be integrated into the granule cell layer of mature monkeys We found that postnatal neurogenesis has a similar potential in rats and monkeys ie the renewal of the entire population of granule cells during an individualrsquos lifetime It is therefore likely to be the case in humans as well

Maturation of Distinct Hippocampal CircuitsIn a second quantitative study of the postnatal structural development of the monkey hippocampal formation [14] we showed that distinct hippocampal regions and lay-ers exhibit different profiles of structural development during early postnatal life

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(fig 2) Specifically we found a protracted period of neuron addition in the dentate gyrus throughout the first postnatal year (see above) and a concomitant late matura-tion of the granule cell population and individual dentate gyrus layers that extended beyond the first year of life Together with the late maturation of the granule cells it has been reported that the mossy cells the major targets of the granule cell projec-

Infant Juvenile Adult

CA3 CA2 CA1 Sub

PrS PaS

Newborn3 months6 months9 months1 year5ndash10 years

Retro-splenialcortex

Subcorticalstructures

Entorhinal IIcortex III VndashVI

Septummammillary

nuclei

PrS PaS

Septummammillary

nuclei

PrS PaS

Septummammillary

nuclei

PrS PaS

Fig 2 a Volume of individual regionslayers of the rhesus monkey hippocampal formation at dif-ferent ages during early postnatal development (expressed as percentage of the volume of the layerregion observed in 5- to 10-year-old monkeys averages plusmn standard errors of the mean) b Hierarchical model of the postnatal maturation of the primate hippocampal formation ATN = Anterior thalamic nuclei DG = dentate gyrus CA3 CA2 CA1 = fields of the hippocampus proper Sub = subiculum PrS = presubiculum PaS = parasubiculum II III V VI = layers of the entorhinal cortex

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tions in the polymorphic layer exhibit clear morphological changes in soma and dendritic structure until at least 9 months of age in monkeys [19] and at least 30 months of age in humans [20] Indeed our analyses revealed a 25 increase in vol-ume of the polymorphic layer between 1 year and 5ndash10 years of age in monkeys Al-though the postnatal development of the polymorphic layer circuits is likely delayed as compared to that of the dentate gyrus afferents reaching the molecular layer de-tailed analyses of the postnatal maturation of the different cell types contained in the dentate gyrus will be necessary to provide a definite answer regarding the functional consequences of this delayed maturation This information is particularly important to further our understanding of the etiology of temporal lobe epilepsy as a prominent theory suggests that acquired epilepsy is an immediate network defect caused primar-ily by initial neuron loss during early postnatal life most likely a loss of dentate gyrus mossy cells [21]

The development of CA3 generally parallels that of the dentate gyrus However the distal portion of CA3 which receives direct entorhinal cortex projections matures earlier than the proximal portion of CA3 At the cellular level we found that the prox-imal CA3 pyramidal neurons exhibit significant changes in soma size within the first 3ndash6 postnatal months In contrast the size of distal CA3 pyramidal neurons does not vary during postnatal development Our quantitative data are thus in agreement with the qualitative report by Seress and Ribak [22] showing that the somas and dendrites of distal CA3 pyramidal neurons exhibit adult-like ultrastructural features at birth To our knowledge there is no published information on the ultrastructural characteris-tics of developing proximal CA3 pyramidal neurons

CA1 matures relatively earlier than the dentate gyrus and CA3 despite the fact that CA3 pyramidal neurons contribute the largest projection to CA1 pyramidal neurons Interestingly CA1 stratum lacunosum-moleculare in which direct entorhinal cortex projections terminate matures earlier than CA1 strata oriens pyramidale and radia-tum in which the CA3 projections terminate Our quantitative measurements are in agreement with qualitative reports of a later myelination of fibers in strata pyrami-dale and radiatum as compared to stratum lacunosum-moleculare in CA1 of hu-mans [23]

The subiculum develops earlier than the dentate gyrus CA3 and CA1 but not CA2 However similar to CA1 the molecular layer of the subiculum in which the entorhi-nal cortex projections terminate is overall more mature in the first postnatal year as compared to the stratum pyramidale in which most of the CA1 projections terminate Unlike other hippocampal fields volumetric measurements suggest regressive events in the structural maturation of presubicular neurons and circuits Finally areal and neuron soma size measurements reveal an early maturation of the parasubiculum Two unique features of these structures as compared to other hippocampal regions are their reciprocal connections with the anterior thalamic nuclear complex and their heavy cholinergic innervation Accordingly cell circuits in the presubiculum and parasubiculum might contribute to some of the earliest functions subserved by the

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hippocampal formation (fig 2) A detailed discussion of the implications of these findings with respect to the emergence of distinct lsquohippocampus-dependentrsquo memory processes in humans can be found in [24]

What Animals Can Teach Clinicians about Hypoxic Lesions and Febrile Seizures

In an effort to understand the molecular basis of the normal development of the hip-pocampal formation and its susceptibility to a number of different pathologies we launched a series of experiments examining the regulation of gene expression in dis-tinct regions of the monkey hippocampal formation during postnatal development In a first study [25] we characterized the molecular signature of individual hippocam-pal regions in an attempt to understand the paradox that although the hippocampus plays a central role in the brain network essential for memory function it is also the brain structure that is most sensitive to hypoxic-ischemic episodes We found that the expression of genes associated with glycolysis and glutamate metabolism in astrocytes as well as the coverage of excitatory synapses by astrocytic processes undergo signifi-cant decreases in the CA1 field of the monkey hippocampus specifically during post-natal development (fig 3)

Taken together our findings at the gene protein and structural levels suggest that the developmental decrease in astrocytic processes and functions may be the critical factor underlying the selective vulnerability of CA1 to hypoxic-ischemic episodes in adulthood They also provide an explanation for the relative resistance of this brain structure to hypoxia in the perinatal period and in particular during the birth pro-cess In newborns high astrocytic coverage likely maintains sufficient glutamate reup-take to limit neuronal depolarization and excitotoxicity during mild-to-moderate hy-poxic-ischemic events In the adult however a lower expression level of genes associ-ated with glycolysis or glutamate uptake and metabolism as well as a lower astrocytic coverage of excitatory synapses in CA1 may render the system more vulnerable to a reduction in oxygen concentration

In contrast a major benefit that derives from decreased astrocytic coverage in adulthood is the regulation of synaptic efficacy leading to an increase in synaptic se-lectivity advantageous for learning Thus a developmental decrease of astrocytic pro-cesses and functions may therefore contribute to the emergence of adult-like selective memory function [24 25]

Finally the relatively high astrocytic coverage of the newborn synapses may also play a central role in the generation of febrile seizures The highest incidence of sei-zures is in the first 2 years of life in humans and is most often associated with a febrile illness Fever begins with the activation of immune response cells that produce inter-leukin-1 which in turn increases prostaglandin E2 synthesis Prostaglandins act at the level of the hypothalamus to regulate body temperature and induce fever Interest-ingly prostaglandins also stimulate calcium-dependent glutamate release in astro-

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010203040

706050

Newborn

6 month

earAdult

DG CA3 CA1 Sub

Newborn6 months1 yearAdult

Newborn

6 month

earAdult

Astrocytic processes

Febrile seizures

Hypoxic lesionsNewborn Adult

Newborn

Astrocyt

Neuron

Presyn

Astrocyt

Neuron

Presyn

Fig 3 a Microarray analysis of gene expression in the rhesus monkey hippocampal formation GFAP gene expression decreased from birth to 6 months of age in CA1 GFAP gene expression decreased after 1 year of age in CA3 GFAP gene expression did not differ between CA3 and CA1 at birth but differed at all other ages EC = Entorhinal cortex DG = dentate gyrus CA3 and CA1 = fields of the hippocampus Sub = subiculum b GFAP immunostaining in the rhesus monkey hippocampus GFAP immunostaining decreased from birth to 6 months of age in CA1 GFAP immunostaining decreased after 1 year of age in CA3 GFAP immunostaining did not differ between CA3 and CA1 at birth but differed at all other ages all p lt 005 c Electron microscope evaluation of astrocytic processes around excitatory synapses in the stratum radiatum of CA1 in rhesus monkeys The surface area oc-cupied by astrocytic processes decreased from birth to adulthood p = 00039 d Schematic rep-resentation of the changes in glial processes and putative functions from birth to adulthood and the associated risks of exhibiting febrile seizures or suffering from hypoxic-ischemic lesions

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cytes which can induce abnormal prolonged depolarization with repetitive spiking in CA1 pyramidal neurons leading to seizures Thus the relatively high astrocytic cover-age of the dense network of CA1 excitatory synapses in the newborn (twice that of the adult) could explain why infants exhibit a higher incidence of febrile seizures Con-versely the decrease in the astrocytic coverage of hippocampal excitatory synapses with development might provide the cellular basis for the decreased susceptibility to febrile seizures with age We refer the reader to our original article [25] for a detailed discussion of the cellular mechanisms involved in these processes

What Animals Can Teach Clinicians about Schizophrenia

Our neuroanatomical and gene expression studies described above identified differ-ent periods of postnatal development during which pathogenic factors might impact the structural and functional maturation of distinct regions of the primate hippocam-pal formation The implications of our findings for autism spectrum disorders tem-poral lobe epilepsy and Down syndrome have been discussed previously [4] Here we focus on detailed analyses of specific patterns of gene expression and the perspec-tives that our findings in monkeys provide to comprehending the etiology of schizo-phrenia in humans [26 27]

Pathological Findings in HumansMRI studies consistently report reduced hippocampal volumes in first-episode schizo-phrenic subjects [28] and asymptomatic first-degree relatives of subjects with schizo-phrenia [29] indicating that hippocampal pathology is not the result of the illness or treatment but rather contributes to the etiology of the disorder Consistent neuro-pathological findings include alterations in markers of synaptic transmission for both glutamatergic and GABAergic systems [30 31] in particular in proximal CA3 [32] Interestingly there are no changes in the total number of hippocampal neurons and reports concerning neuron density or cell size differences are rather inconsistent In contrast there are reliable morphological changes in the dendritic and axonal arbori-zation of dentate granule cells and the synaptic organization of CA3 pyramidal neu-rons Specifically the frequency of granule cells with basal dendrites is higher and the CA3 mossy fiber synapses are both smaller and fewer in schizophrenic patients as compared to controls These findings together with the absence of obvious signs of neurodegeneration [30] suggest that schizophrenia is a neurodevelopmental disorder that might arise following the abnormal maturation of specific hippocampal circuits namely the dendritic and axonal arborization of dentate granule cells

As described above our morphological data indicate that the dentate gyrus ma-tures late after all the other hippocampal regions Pathogenic factors which remain to be determined might therefore impact the maturation of the dentate granule cells and their projections to CA3 pyramidal neurons during postnatal life However the

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absence of obvious disorganization of the dentate granule cell layer in schizophrenia suggests that pathogenic factors might act after the initial phase of postnatal develop-mental neurogenesis and neuron addition to the granule cell layer (ie a period cor-responding to at least the first postnatal year in monkeys) Pathogenic factors influ-encing gene expression and the maturation of newly generated granule cells during late childhood or early adolescence might therefore contribute to the emergence of schizophrenic symptoms during adolescence Accordingly genetic predispositions to schizophrenia have been shown [30] and the identification of a number of suscepti-bility genes involved in postnatal neurogenesis including DISC1 COMT NRG1 and NPAS3 provides an additional link between the regulation of postnatal granule cell maturation and schizophrenia

Regulation of Gene Expression in MonkeysThe hypothesis that schizophrenia emerges from the interaction between genetic pre-dispositions and environmental factors is now widely accepted [33] The genetic com-ponent of schizophrenia was first suspected since relatives of subjects with schizo-phrenia are more likely to get the illness themselves Indeed the risk of suffering from schizophrenia in the general population is about 1 People who have a third-degree relative (great grandparent first cousin) with schizophrenia are twice as likely to de-velop schizophrenia (2) and those with a second-degree relative (grandparent un-cle aunt) have an incidence varying from 2 to 6 Finally first-degree relatives (par-ent sibling) have an incidence of schizophrenia gt10 times higher than the general population (13 for children 17 for twins 48 for identical twins) Accordingly linkage analysis gene expression and genome-wide association studies have identi-fied a number of schizophrenia susceptibility genes

We analyzed the expression of 173 schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development in order to assess the contribution of these genes to the normal development of the hip-pocampal formation and shed light on the pathogenesis of schizophrenia [26] We further considered schizophrenia susceptibility genes involved in other diseases in-cluding temporal lobe epilepsy autism spectrum disorder Williams syndrome psy-chopathy major depressive disorder bipolar disorder and Alzheimerrsquos disease to gain a better understanding of the possible relations between gene dysregulation neu-ropathology and clinical symptoms We found that as compared with all human protein-coding genes schizophrenia susceptibility genes exhibit a differential regula-tion of expression in the dentate gyrus CA3 and CA1 over the course of postnatal development (fig 4) These findings are consistent with the hypothesis that hippo-campal subfield dysfunctions could underlie psychotic manifestations in schizophre-nia [34] A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3 Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms such as loosening of association Interestingly changes in gene expression

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in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms We also found earlier changes in expression of schizophrenia sus-ceptibility genes in CA1 which might be linked to prodromal psychotic symptoms Finally a number of schizophrenia susceptibility genes including APOE BDNF MTHFR and SLC6A4 are involved in other disorders and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis

101520

353025

404550

EC DG CA3 CA1 Suba

101520

353025

404550

EC DG CA3 CA1 Subb

063 042

Schizophrenia genesAll genes

Newborn

6 month

6ndash12

Newborn

6 month

6ndash12

Newborn

6 month

6ndash12

Fig 4 Percentages of schizophrenia susceptibility genes regulated in distinct hippocampal regions from birth to adulthood decreased expression (a) and increased expression (b) Schizophrenia sus-ceptibility genes (173 dark gray) protein-coding human genes (20741 light gray) DG = Dentate gyrus EC = entorhinal cortex Sub = subiculum c Expression patterns of schizophrenia susceptibil-ity genes regulated in the dentate gyrus CA3 and CA1 from birth to adulthood Dentate gyrus 33 schizophrenia susceptibility genes exhibited lower expression levels in adult than newborn mon-keys CA3 34 schizophrenia susceptibility genes (63 solid lines) exhibit a significantly lower ex-pression in adults than at any other ages CA1 35 schizophrenia susceptibility genes (52 solid lines) are significantly more expressed at birth than at any other ages Averages plusmn standard errors of the mean

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We also used predictive bioinformatics analyses to decipher the mechanisms that underlie the coregulation of expression of hundreds of genes in different cell types at specific ages in distinct hippocampal regions [27] Our analyses suggested that miRNAs (small RNA molecules acting as posttranscriptional regulatory ele-ments which have been shown to play a major role in developmental processes) may contribute to the coregulation of gene expression in different cell types (ie in neurons astrocytes oligodendrocytes) at different postnatal ages in distinct regions of the developing monkey hippocampus Interestingly 65 of these predicted miRNAs are conserved across species from rodents to humans whereas 35 are specific to primates including humans These miRNAs could contribute to some of the structural and functional differences observed between primate and nonpri-mate mammals For example the differences in dendritic morphology of CA1 neu-rons observed between rats and monkeys [8] could be related to the regulation of genes like CTNNA2 (coding for the protein alpha-N-catenin) whereas GNB5 (cod-ing for the guanine nucleotide-binding protein beta-5) regulation may produce differences in the electrophysiological characteristics of hippocampal neurons be-tween these two species Indeed these genes were predicted to be preferentially targeted by primate-specific miRNAs and are involved respectively in dendritic morphology and the regulation of the stability of synaptic contacts and in the elec-trophysiological properties of neurons Other differences found among primate species might be related to the further evolution of these primate-specific miRNAs Indeed the numbers of miRNAs in the miR-548 and C19MC families increase from Macaca mulatta and Pongo pygmaeus to Pan troglodytes and Homo sapiens Such species differences in miRNAs might lead to subtle differences in the regulation of gene expression that might underlie species differences in hippocampal structure and function that have emerged over the course of evolution These differences might be particularly important to consider when extrapolating from experimental results in model animals such as rodents and monkeys to clinical applications in humans

Conclusion

Experimental work performed with animals in particular rodents but also monkeys has provided most of our knowledge regarding the structural organization of func-tional hippocampal circuits Similarly animal models are typically used to study the molecular and cellular basis of pathologies affecting human hippocampal structure and function It is therefore important to be aware of the similarities and differences between species (eg rats monkeys humans) in order to extrapolate from the findings of fundamental research in animals to clinical investigations in humans Here we dis-cussed specific findings regarding the normal postnatal development of the monkey hippocampal formation which provide an essential framework to consider the eti-

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egraveque

ologies of different neuropathological disorders affecting human hippocampal struc-tures and functions We argued that researchers as well as clinicians should not con-sider the use of animals in research only as lsquoanimal modelsrsquo of human diseases as they will continue to need and benefit from a better understanding of the normal structure and function of the hippocampus in lsquomodel animalsrsquo

Acknowledgements

This work was supported by grants from the Swiss National Science Foundation (PP00A-106701 PP00P3-124536) and the National Alliance for Research on Schizophrenia and Depression (NARSAD)

References

1 Amaral DG Andersen P Bliss T Morris RGM OrsquoKeefe J The Hippocampus Book Oxford Oxford University Press 2007

2 Amaral DG Lavenex P Hippocampal neuroanato-my in Amaral DG Andersen P Bliss T Morris RGM OrsquoKeefe J (eds) The Hippocampus Book Ox-ford Oxford University Press 2007 pp 37ndash114

3 Lavenex P Neuroanatomic organization and funda-mental functions of the hippocampus and amygdala in Riva D Njiokiktjien C Bulgheroni S (eds) Brain Lesion Localization and Developmental Functions Montrouge John Libbey Eurotext Ltd 2011 pp 89ndash118

4 Lavenex P Functional anatomy development and pathology of the hippocampus in Bartsch T (ed) Clinical Neurobiology of the Hippocampus Oxford University Press 2012

5 Banta Lavenex P Amaral DG Lavenex P Hippo-campal lesion prevents spatial relational learning in adult macaque monkeys J Neurosci 2006 26 4546ndash4558

6 Banta Lavenex P Lavenex P Spatial memory and the monkey hippocampus not all space is created equal Hippocampus 2009 19 8ndash19

7 Lavenex P Banta Lavenex P Amaral DG Postnatal development of the primate hippocampal formation Dev Neurosci 2007 29 179ndash192

8 Altemus KL Lavenex P Ishizuka N Amaral DG Morphological characteristics and electrophysio-logical properties of CA1 pyramidal neurons in macaque monkeys Neuroscience 2005 136 741ndash756

9 Lavenex P Banta Lavenex P Bennett JL Amaral DG Postmortem changes in the neuroanatomical char-acteristics of the primate brain hippocampal forma-tion J Comp Neurol 2009 512 27ndash51

10 Vargha-Khadem F Gadian DG Watkins KE Con-nelly A Van Paesschen W Mishkin M Differential effects of early hippocampal pathology on episodic and semantic memory Science 1997 277 376ndash380

11 Squire LR Zola SM Structure and function of de-clarative and nondeclarative memory systems Proc Natl Acad Sci USA 1996 93 13515ndash13522

12 Lavenex P Banta Lavenex P Amaral DG Spatial re-lational learning persists following neonatal hippo-campal lesions in macaque monkeys Nat Neurosci 2007 10 234ndash239

13 Jabegraves A Banta Lavenex P Amaral DG Lavenex P Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gy-rus Eur J Neurosci 2010 31 273ndash285

14 Jabegraves A Banta Lavenex P Amaral DG Lavenex P Postnatal development of the hippocampal forma-tion a stereological study in macaque monkeys J Comp Neurol 2011 519 1051ndash1070

15 Altman J Das GD Autoradiographic and histologi-cal evidence of postnatal hippocampal neurogenesis in rats J Comp Neurol 1965 124 319ndash336

16 Rakic P Nowakowski RS The time of origin of neu-rons in the hippocampal region of the rhesus mon-key J Comp Neurol 1981 196 99ndash128

17 Eriksson PS Perfilieva E Bjork-Eriksson T Alborn A-M Nordborg C Peterson DA et al Neurogenesis in the adult human hippocampus Nat Med 1998 4

1313ndash131718 Seress L Morphological changes of the human hip-

pocampal formation from midgestation to early childhood in Nelson CA Luciana M (eds) Hand-book of Developmental Cognitive Neuroscience Cambridge MIT Press 2001 pp 45ndash58

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egraveque

19 Seress L Ribak CE Postnatal development and syn-aptic connections of hilar mossy cells in the hippo-campal dentate gyrus of rhesus monkeys J Comp Neurol 1995 355 93ndash110

20 Seress L Mrzljak L Postnatal development of mossy cells in the human dentate gyrus a light microscopic Golgi study Hippocampus 1992 2 127ndash141

21 Sloviter RS Experimental status epilepticus in animals what are we modeling Epilepsia 2009

50(suppl 12)11ndash1322 Seress L Ribak CE Postnatal development of CA3

pyramidal neurons and their afferents in the Am-monrsquos horn of rhesus monkeys Hippocampus 1995

5 217ndash23123 Abraham H Vincze A Jewgenow I Veszpremi B

Kravjak A Gomori E et al Myelination in the hu-man hippocampal formation from midgestation to adulthood Int J Dev Neurosci 2010 28 401ndash410

24 Lavenex P Banta Lavenex P Building hippocampal circuits to learn and remember insights into the de-velopment of human memory Behav Brain Res 2013 254 8ndash21

25 Lavenex P Sugden SG Davis RR Gregg JP Banta Lavenex P Developmental regulation of gene ex-pression and astrocytic processes may explain selec-tive hippocampal vulnerability Hippocampus 2011

21 142ndash14926 Favre G Banta Lavenex P Lavenex P Developmen-

tal regulation of expression of schizophrenia suscep-tibility genes in the primate hippocampal formation Transl Psychiatry 2012 2e173

27 Favre G Banta Lavenex P Lavenex P miRNA regu-lation of gene expression a predictive bioinformatics analysis in the postnatally developing monkey hip-pocampus PLoS One 2012 7e43435

28 Steen RG Mull C McClure R Hamer RM Lieber-man JA Brain volume in first-episode schizophre-nia systematic review and meta-analysis of magnet-ic resonance imaging studies Br J Psychiatry 2006

188 510ndash51829 Sismanlar SG Anik Y Coskun A Agaoglu B Kara-

kaya I Yavuz CI The volumetric differences of the fronto-temporal region in young offspring of schizo-phrenic patients Eur Child Adolesc Psychiatry 2010

19 151ndash15730 Harrison PJ The hippocampus in schizophrenia a

review of the neuropathological evidence and its pathophysiological implications Psychopharmacol-ogy (Berl) 2004 174 151ndash162

31 Talbot K Eidem WL Tinsley CL Benson MA Thompson EW Smith RJ et al Dysbindin-1 is re-duced in intrinsic glutamatergic terminals of the hippocampal formation in schizophrenia J Clin In-vest 2004 113 1353ndash1363

32 Harrison PJ Law AJ Eastwood SL Glutamate recep-tors and transporters in the hippocampus in schizo-phrenia Ann NY Acad Sci 2003 1003 94ndash101

33 Maric NP Svrakic DM Why schizophrenia genetics needs epigenetics a review Psychiatr Danub 2012

24 2ndash1834 Tamminga CA Stan AD Wagner AD The hippo-

campal formation in schizophrenia Am J Psychiatry 2010 167 1178ndash1193

Prof Dr Pierre LavenexLaboratory for Experimental Research on Behavior Institute of PsychologyUniversity of Lausanne Geacuteopolis 4343CHndash1015 Lausanne (Switzerland)E-Mail pierrelavenexunilch

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garding the basic structure and functions of the hippocampal formation have derived from animal studies [1] Over the years however a gradual shift has occurred in the type of scientific studies performed with animals going from descriptive studies of the organization of the nervous system to experimental studies of normal brain func-tion to animal models of human disease

Currently a prominent ill-conceived view of which research with animals should be encouraged funded or even allowed posits that scientists should be restricted to only using animal models of human diseases that can lead to results applicable to humans within a few years Although there is no doubt that translational studies of this kind are important and necessary limiting animal studies to currently appli-cable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems Moreover defining what is dis-pensable in science and foreseeing which experiment will lead to truly applicable results are very difficult and often likely to be wrong Failure is part of the scien-tific endeavor and should be embraced as much as success as long as we have a chance to gain new knowledge by performing an experiment or making an obser-vation

A perfect example of this is the discovery of penicillin by Sir Alexander Fleming in 1928 It was a failed experiment the accidental contamination of a bacteria cul-ture plate by a mold that led to the isolation and identification of this widely-used antibacterial substance In his Nobel Prize acceptance speech in 1945 Fleming de-clared

We all know that chance fortune fate or destiny ndash call it what you will has played a consider-able part in many of the great discoveries in science We do not know how many for all scientists who have hit on something new have not disclosed exactly how it happened We do know though that in many cases it was a chance observation which took them into a track which eventually led to a real advance in knowledge or practice This is especially true of the biological sciences for there we are dealing with living mechanisms about which there are enormous gaps in our knowl-edge

Many scientists including a number of other Nobel laureates have shared his view Furthermore to date there are still enormous gaps in our knowledge of normal brain structure and functions

Here we very humbly discuss the continuous need to obtain fundamental infor-mation regarding how the normal brain is built and works We argue that researchers as well as clinicians should not consider the use of animals in research only as lsquoanimal modelsrsquo of human diseases since science and medicine in particular will continue to need and indeed will benefit greatly from a better understanding of the structure and function of biological systems in various organisms or lsquomodel animalsrsquo Given the fo-cus of this book on the hippocampus we consider specific examples illustrating how fundamental knowledge of the normal patterns of postnatal development of the mon-key hippocampal formation can shed light on the etiologies of human diseases affect-ing hippocampal structure and function

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Rat Monkey Human

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CA3 CA2 CA1 Sub

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Acknowledgements

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Acknowledgements

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Acknowledgements

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Conclusion

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Acknowledgements

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Documents

[Frontiers of Neurology and Neuroscience] The Hippocampus in Clinical Neuroscience Volume 34 () || What Animals Can Teach Clinicians about the Hippocampus